THE RATIONALE FOR USE OF INCRETINS IN THE MANAGEMENT OF NEW ONSET DIABETES AFTER TRANSPLANTATION (NODAT).

OBJECTIVE: Owing to advances in transplant science, increasing numbers of patients are receiving solid organ transplantation. New onset diabetes after transplantation (NODAT) frequently develops in transplant patients and requires acute and often ongoing management of hyperglycemia. The metabolic derangements of NODAT are similar to those of classic type 2 diabetes, and treatment has typically followed diabetes standards of care. Best practices for NODAT management remain to be developed. METHODS: The mechanistic suitability of incretins to treat NODAT pathogenesis has been hitherto underappreciated. This review details the specific mechanistic value of incretins in patients with immunosuppression-associated hyperglycemia. RESULTS: Corticosteroids have long been known to exert their effects on glucose metabolism by decreasing glucose utilization and enhancing hepatic gluconeogenesis. Corticosteroids also significantly and directly reduce insulin secretion, as do calcineurin inhibitors (CNIs), another commonly used group of immunosuppressive drugs that cause hyperglycemia and NODAT. The ability of incretins to counteract immunosuppressant-induced disruptions in insulin secretion suggest that the insulinotropic, glucagonostatic, and glucose-lowering actions of incretins are well suited to treat immunosuppressant-induced hyperglycemia in NODAT. Additional benefits of incretins include decreased glucagon levels and improved insulin resistance. In the case of glucagon-like peptide-1 (GLP-1) receptor agonists, weight loss is another benefit, countering the weight gain that is a common consequence of both hyperglycemia and transplantation. These benefits make incretins very attractive and deserving of more investigation. CONCLUSION: Among diabetes treatment options, incretin therapies uniquely counteract immunosuppressant drugs' interference with insulin secretion. We propose an incretin-based treatment paradigm for NODAT management.

Gluco-regulation & type 2 diabetes: entrenched misconceptions updated to new governing principles for gold standard management.

Our understanding of type 2 diabetes (T2D) has evolved dramatically. Advances have upended entrenched dogmas pertaining to the onset and progression of T2D, beliefs that have prevailed from the early era of diabetes research-and continue to populate our medical textbooks and continuing medical education materials. This review article highlights key insights that lend new governing principles for gold standard management of T2D. From the historical context upon which old beliefs arose to new findings, this article outlines evidence and perspectives on beta cell function, the underlying defects in glucoregulation, the remediable nature of T2D, and, the rationale supporting the shift to complication-centric prescribing. Practical approaches translate this rectified understanding of T2D into strategies that fill gaps in current management practices of prediabetes through late type 2 diabetes.

Intersections and Clinical Translations of Diabetes Mellitus with Cancer Promotion, Progression and Prognosis.

The association between cancer and dysglycemia has been well documented. It is underappreciated, however, that sustained dysglycemia could potentially be a catalyst toward a pro-cancer physiologic milieu and/or increase the burden of cancer. Hyperglycemia, hyperinsulinemia and energy metabolism at large impact a cascade of growth pathways, epi/genetic modifications, and mitochondrial changes that could feasibly link to tumor processes. Oxidative stress is a recurring motif in cell dysfunction: in diabetes, oxidative stress and reactive oxygen species (ROS) feature prominently in the damage and demise of pancreatic beta cells, as well as cell damage contributing to diabetes-related complications. Oxidative stress may be one intersection at which metabolic and oncogenic processes cross paths with deleterious results in the development of precancer, cancer, and cancer progression. This would augur for tight glucose control. Regrettably, some medical societies have recently relaxed hemoglobin A1c targets. A framework for the hyperglycemic state is presented that helps account and translate the full scope of effects of dysglycemia to ultimately improve clinical best practices.

Type 2 diabetes: Evolving concepts and treatment.

In view of new information, we are revising the way we think about and treat diabetes mellitus. In this new view, the insulin-producing beta cells are key, and preserving beta-cell function is paramount. These insights, together with recent outcome studies provide compelling arguments regarding treatments of choice.

Insulin Therapy Increases Cardiovascular Risk in Type 2 Diabetes.

Insulin therapy increased cardiovascular (CV) risk and mortality among type 2 diabetes (T2D) patients in several recently reported clinical outcomes trials. To assess whether this association is causative or coincidental, PubMed searches were used to query the effects of insulin therapy for T2D on CV health and longevity from large-scale outcomes trials, meta-analyses, and patient registry studies, as well as basic research on insulin's direct and pleiotropic actions. Although several old studies provided conflicting results, the majority of large observational studies show strong dose-dependent associations for injected insulin with increased CV risk and worsened mortality. Insulin clearly causes weight gain, recurrent hypoglycemia, and, other potential adverse effects, including iatrogenic hyperinsulinemia. This over-insulinization with use of injected insulin predisposes to inflammation, atherosclerosis, hypertension, dyslipidemia, heart failure (HF), and arrhythmias. These associations support the findings of large-scale evaluations that strongly suggest that insulin therapy has a poorer short- and long-term safety profile than that found to many other anti-T2D therapies. The potential adverse effects of insulin therapy should be weighed against proven CV benefits noted for select other therapies for T2D as reported in recent large randomized controlled trials.

A Unified Pathophysiological Construct of Diabetes and its Complications.

Advances in understanding diabetes mellitus (DM) through basic and clinical research have helped clarify and reunify a disease state fragmented into numerous etiologies and subtypes. It is now understood that a common pathophysiology drives the diabetic state throughout its natural history and across its varied clinical presentations, a pathophysiology involving metabolic insults, oxidative damage, and vicious cycles that aggravate and intensify organ dysfunction and damage. This new understanding of the disease requires that we revisit existing diagnostics and treatment approaches, which were built upon outmoded assumptions. 'The Common Pathophysiologic Origins of Diabetes Mellitus and its Complications Construct' is presented as a more accurate, foundational, and translatable construct of DM that helps make sense of the hitherto ambiguous findings of long-term outcome studies.

Obviating much of the need for insulin therapy in type 2 diabetes mellitus: A re-assessment of insulin therapy's safety profile.

Current processes of care for diabetes mellitus (DM) were shaped during the era when insulin therapy was considered inexorable to the management of advanced stage type 2 (T2DM), though this no longer appears to be categorically true. There are also dashed hopes that insulin therapy can prevent or stall diabetes. While exogenous insulin remains a life-sparing tool for fully insulin-dependent DM, insulin therapy-induced hyperinsulinemia now appears to contribute to serious safety issues beyond hypoglycemia and weight gain. Iatrogenic and compensatory hyperinsulinemia are metabolic disruptors of ß-cells, liver, muscle, kidney, brain, heart and vasculature, inflammation, and lipid homeostasis, among other systems. This may compromise ß-cells, exacerbate insulin resistance (IR), and increase risk of cardiovascular (CV) disease. Striking associations between exogenous insulin and risks of CV events, cancer, and all-cause mortality in clinical trial and real-world cohorts caution that insulin may pose more harm than previously evidenced. At our disposal are numerous alternate tools that, alone or in combination, efficaciously manage hyperglycemia and glucolipotoxicity, and do so without inducing hypoglycemia, weight gain, or hyperinsulinemia. Moreover, these new tools support true precision therapy, as modern day drug classes can be aligned with the various mediating pathways of hyperglycemia at work in any given patient. Some also appear to promote ß-cell survival, with intriguing data being presented for newer agents, such as incretins. As such, we encourage preferential use of non-insulin antidiabetic agents to injected insulin for the management of non-insulin-dependent patients with T2DM, including in advanced stage T2DM. The goal of this article is to augment existing literature to 1) correct misconceptions on the rationale and necessity for insulin therapy in T2DM, 2) discuss emerging negative safety data with insulin therapy, and, 3) offer a practical means to reduce reliance on insulin through delayed initiation, minimized dose, and, drug switching to safer agents, and, potentially, reframes processes of care.

Health economic considerations in the management of type 2 diabetes.

The number of therapeutic options for people with type 2 diabetes is increasing. Large-scale clinical trials have delineated the health benefits of tight glycemic control with these interventions, including the reduction of long-term diabetes-related complications. These long-term complications compromise quality of life and ultimately account for mortality in most patients with diabetes. Despite the high price tag of managing the long-term complications of hyperglycemia, few economic incentives have been presented for investing in intensive glycemic control. Recent cost-benefit analyses, however, provide insight into the major cost drivers that yield a short-term return on investment for preventive measures. This article highlights cost-effective measures that have been successfully utilized in the managed care setting to simultaneously improve health and economic outcomes of diabetes within the first few years of implementation.